Organic Chemistry of Drug Synthesis. Volume 7

115 with methylamine gives intermediate 116. Acylation of the secondary
amine with pivaloyl chloride affords the corresponding amide and thus the
endothelin receptor antagonistedonentan( 117 ).^18

Br

SO 2 Cl

108

+

ON

H 2 N CH 3

CH 3

109

Br ON

NH CH

3

OS 2 CH^3

110

Br ON

N CH

3

OS 2 CH^3

MOM

111 ; MOM = CH 3 OCH 2

(CH 3 O) 2 B ON

N CH 3

OS 2 CH 3

MOM

1. BuLi


2. (CH 3 O) 3 B

H+

(HO) 2 B ON

N CH

3

OS 2 CH^3

MOM

O = HC 113 112

O N

114 Br

ON

NH CH

3

O = HC OS 2 CH 3

O N

Pd, (C 6 H 5 ) 3 P

CH 3 NH 2

[H] O

N

NH CH 3

OS 2 CH 3

O N

HN

H 3 C ON

NH CH

3

OS 2 CH^3

O N

H N

3 C

O

115 116 117

Cholesterol is not absorbed from the intestine as such, but needs to be
esterified first. This process requires a special enzyme, ACAT (acyl-
CoA : cholesterol acyltransferase). Inhibitors of this enzyme should
provide a means of reducing serum cholesterol levels by limiting the
amount absorbed from the diet. The inhibitoravasamibe( 125 ) is included
in this section though the sulfur-containing function, which comprises an
unusual sulfonamide linked through oxygen rather than carbon.
Chloromethylation of commercially available 1,3,5-triisopropylbenzene
( 118 ) with formaldehyde and hydrogen chloride affords the chloromethy-
lated derivative ( 119 ). Displacement of the benzylic chlorine by cyanide
gives the corresponding nitrile ( 120 ). The cyano group is then hydrolyzed
with base to give the arylacetic acid ( 121 ). The other branch of the conver-
gent synthesis starts with reaction of the hindered phenol ( 122 ) with
isocyanosulfonyl chloride to give the O-sulfonated product ( 123 ).
Hydrolysis then leads toO-sulfonamide ( 124 ). Acylation of intermediate
124 with the acid chloride obtained from acid 122 and thionyl chloride
leads to the ACAT inhibitor ( 125 ).^19

56 MONOCYCLIC AROMATIC COMPOUNDS